A significant population of smokers is unable or unwilling to quit smoking. As a consequence, strategies to reduce toxin exposure are being considered as a potential means of reducing tobacco-related morbidity and mortality. The purpose of this research project will be to continue to systematically examine the amount of toxin exposure across various reduction strategies and potential reduced exposure products (PREPs) using short-term, well-controlled clinical trials. In our prior TTURC project, we have focused on determining reliable and dose-responsive surrogate biomarkers for tobacco toxin exposure and risk factors for disease, and how different PREPs affect these biomarkers and the achievement of abstinence. We will expand our research efforts to better understand the underlying mechanism associated with different approaches for exposure reduction and explore factors influencing individual differences in treatment response. The focus will be on PREPs that primarily manipulate nicotine dose and closely parallels the animal studies proposed in Project 2 (Nicotine Exposure Reduction in Rats) of this TTURC. The four proposed studies involve: 1) reducing nicotine by reducing the number of cigarettes smoked; 2) reducing nicotine by reducing the nicotine yield of the cigarette smoked vs. nicotine lozenge; 3) reducing nicotine by using an antagonist treatment, nicotine vaccine; and 4) increasing nicotine by using high dose of nicotine patch with or without nicotine-free cigarettes. Subjects will be assessed at baseline, during six weeks of treatment with these products, and then during six weeks of abstinence. The aims of the studies are to examine and compare the effects of these intervention approaches on: 1) biomarkers for tobacco toxin exposure and risk factors for disease; 2) extent of compensatory smoking, a strong determinant of toxin exposure; and 3) different aspects of tobacco addiction (e.g., physical dependence, negative affect, responses to cues, etc.). In addition, factors (genotype and phenotypes) that moderate the extent of exposure and that impact subsequent cessation will also be examined. This project, along with the TTURC projects, will provide important evidence-based data on alternative intervention methods that may potentially reduce mortality and morbidity associated with tobacco use.